Dr A R Rajan, Dr Vikram Singh, Dr Anupama A Bhave, Dr Manish Saha, Dr Arindam Chatterjee.
Mucopolysaccharidosis (MPS) is an inherited lysosomal storage disorder which constitutes a group of heterogeneous disorders that occur due to complete or partial absence of enzymes that breakdown the mucopolysaccharides into simpler forms, this leads to progressive accumulation of glycosaminoglycans (previously called mucopolysaccharides ) in nearly all cell types, tissues and organs. Clinical manifestations include skeletal deformities, organomegaly, cardiomyopathy, severe airway obstruction and, in most patients, neurological decline. We report this case of MPS type II because of its rarity and to highlight the distinctive clinical and radiological features of Hunter syndrome.
Key Words: Glycosaminoglycans, Hunter Syndrome, Mucopolysaccharidosis (MPS) type II, Skeletal Dysostoses.
Mucopolysaccharidosis (MPS) is a heterogeneous group of lysosomal storage disorders that are primarily due to deficiency of the lysosomal enzymes required in metabolism of Glycosaminoglycans (GAGs). There are 13 variants of MPS all of which are inherited as autosomal recessive except Mucopolysaccharidosis type II (Hunter syndrome) which is an extremely rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase [1,2]. Hunter Syndrome was described initially by Charles Hunter, a Canadian physician, who described the rare disease found in two brothers in 1917 . Deficiency of specific enzymes lead to deranged excretion of GAGs products like dermatan sulfate, keratan sulfate, heparan sulfate and chondroitin sulfate and in urine . There is thus far no effective treatment for MPS type II (Hunter syndrome), and focus has been on palliative care. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulfatase is now available . This case highlights the distinctive manifestations of Hunter syndrome.
A nine year old boy, born to non consanguineous parents, presented with abdominal distension of four years’ duration without any abdominal pain, bowel disturbances or vomiting. There was no history of jaundice, seizure, weight loss or anorexia. His bladder habit was normal. There was also a history of joint pain over the hips. He started school at six years of age and was below average in his studies. He had one elder sibling (female) aged 14 years who was normal. On direct questioning there was history of hoarseness of voice and snoring but no history suggestive of sleep apnea. There was also history of recurrent bouts of respiratory infections as well as discharge from the ears.
On examination his head was dolichocephalic with a circumference of 55.5 cm (> 97th centile). He had coarse facial features with a depressed nasal bridge, thick ala nasii, coarse hair, thick lips and macroglossia (Fig.1A). He had thick palms and soles with small stubby fingers with flexion of the distal interphalangeal joint (fig 1B). Anthropometric examination showed his weight was 29 kg,Height 101 cm(< 3rd centile) upper and lower segment ratio of 1/1 .His abdomen was distended with a protruding umbilical hernia (Fig.1B).
Figure 1 : Photograph showing Coarse facial features with a depressed nasal bridge, thick ala nasii, coarse hair, thick lips and macroglossiaThick palms and soles with small stubby fingers with flexion of the distal interphalangeal joint , distended abdomen with a protruding umbilical hernia.
His liver was 08 cm below the right costal margin in the mid-clavicular line, with a firm, sharp margin and a smooth surface with a span of 10 cm. His spleen was palpable 2 cm below the left costal margin in the mid-clavicular line. He had no corneal clouding and his fundus appeared normal. His cardiovascular examination revealed a systolic murmur (Gr II/VI).His chest was symmetrical and breath sounds were normal. Ear exam revealed evidence of past suppurative otitis media bilaterally.
Suspecting MPS, skeletal survey was done. Lateral skull radiograph showed an enlarged and J-shaped sella turcica (Fig. 2 A). Bones of the skull and sutures appeared normal for his age. Anteroposterior & lateral radiograph of the dorsolumbar spine showed anterior beaking (Fig2-B)
Figure 2 -Imaging findings showing enlarged and J-shaped sella turcica, anterior beaking of vertebral bodies, iliac flaring with poorly developed acetabulum and widening of phalanges and metacarpals with proximal tapering of the metacarpals.
Vertebral bodies appeared ovoid due to convexity of the superior and inferior surfaces. Spinal curvature was normal and vertebral body height also appeared normal. Hand-wrist radiograph showed widening of his phalanges and metacarpals with proximal tapering of the metacarpals (Fig.4C). Radiograph of the pelvis – antero-posterior view showed iliac flaring with poorly developed acetabulum (Fig.4D). His hematological parameters showed nutritional anaemia. Biochemical parameters including renal and hepatic functions and calcium levels were normal as was his blood sugar. Thyroid functions and lipid profile were also normal. A 2 D echo showed mild mitral regurgitation with normal ejection fractions. 24 hrs total urinary excretion of Glycosaminoglycans Genetic studies and Enzyme assay for iduronate sulfatase could not be done due to financial constraints. Our diagnosis of Hunter Syndrome (MPSII) was confirmed from his history, clinical examination and skeletal survey.
Mucopolysaccharoidoses are, progressive, hereditary diseases caused by genetic mutations leading to alterations in lysosomal enzymes needed to metabolize glycosaminoglycans (acid mucopolysaccharides). There are 13 variants of MPS of whichMPS II is the only known X-linked MPS disorder. The incidence of MPS II is about 1 in 170,000 live male births. MPS type II is classified into severe (type II, A) and mild (type II, HB) based on the presence or absence of central nervous systemdisease and the length of survival[5,6].The typical patient with MPS II is short with coarse facial features. Arthropathy along with connective tissue involvement leads to joint contractures. Hepatoslenomegaly along with lax abdominal muscles causes abdominal prominence.
Glycosaminoglycans (GAG) are long chains of sugar carbohydrates that help build connective tissues, skin, bone, cartilage and corneas. Glycosaminoglycans (GAG) are also found in the fluid that lubricates joints. Accumulation of GAGs causes thickening of tissue and compromises organ function. The major GAGs are hyaluronan, heparin sulphate, chondroitin-4-sulphate ,keratin sulphate and chondroitin-6-sulphate. Over time, these GAGs accumulate in the blood and connective tissues and results in progressive cellular damage. This alters the appearance, reduces physical abilities, and adversely affects functioning of organs and systems including mental development. Clinically the most consistent features include dysmorphic facies, hepatosplenomegaly, arthropathy with contractures. Dysfunction of pulmonary system, myocardial and valvular dysfunction and neurological involvement are other consistent features. Airway obstruction is caused by deposition of GAGs in the oropharyngeal and tracheo-bronchial tree. This leads to leads to severe airway compromise caused by macroglossia along with supraglottic narrowing and tracheomalacia. Sleep apnoea and airway obstruction is therefore a common presentation in MPS II. Further compromise of the respiratory system due to effects of the disease on the thoracic skeleton also makes management of respiratory illness challenging. Deposition of GAGs in the cardiovascular and reticuloendothelial systems, leads to cardiac valvular dysplasia, cardiomyopathy, and hepatosplenomegaly. Severe skeletal deformities cause limitations of joint mobility.CNS involvement present with reduced learning abilities and variable neurological deficit [1,2,5] is established sulphatase enzyme assay in leukocytes, fibroblasts or plasma, using substrates specific for I2S provides the means to arrive at a definitive diagnosis .Prenatal testing is available for assessing risk of MPS II . Though not routinely advocated in clinical practice due to lack of clinical evidence for efficacy Umbilical cord blood transplant and Bone marrow transplant (BMT) offer possible curative options for MPS. Enzyme replacement therapy (ERT) is emerging as a new treatment modality. United States and European Unions have recently approved the use of idursulfatase (Elaprase), for the management of MPS type II. It is recommended to be given as weekly intravenous infusion over at a dose of 0.5 mg/kg[8,9]. However, these definitive treatments are not readily available in many developing countries and supportive care is mainstay of therapy attempting to reduce morbidity in these patients. This includes physiotherapy to mobilize the joints, good nutrition, prevention and prompt treatment of infections, and management of cardio respiratory complications.
CONCLUSION: Mucopolysaccharidosis (MPS) is an inherited lysosomal storage disorder which constitutes a group of heterogeneous disorders. Prenatal diagnosis using villous sampling and amniocentesis should be offered in subsequent pregnancies to detect the possibility of a fetus being affected with the disorder. Genetic counseling can assist parents with a family history of MPS to determine if they are carrying the mutated gene.
1. Kliegman RM, Behrman RE, Jenson HB, Stanton FB. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders; 2010. p. 509-515.
2. Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Mufioz V, Muenzer J: Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008, 121(2):377-386.
3. Hunter C. A rare disease in two brothers. Proc of the Soc Med 1917; 10:104-16
4. Hoffmann B, Schulze-Frenking G, Al-Sawaf S, Beck M, Mayatepek E. Hunter disease before and during enzyme replacement therapy. Pediatr Neurol. 2011;45(3):181-4.
5. Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Mufioz V, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008;121:377-86.
6. Tylki-Szymańska A. Mucopolysaccharidosis type II, Hunter’s syndrome. Pediatr Endocrinol Rev. 2014; 12 Suppl 1:107-13.
7. Cooper A,Thornley M, Wraith JE (1991) First-trimester diagnosis of Hunter syndrome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus. Prenat Diagn 11:731–735
8. Noh H, Lee JI. Current and potential therapeutic strategies for mucopolysaccharidoses. J Clin Pharm Ther 2014;39 (3):215-24.
9. Guillén-Navarro E, Blasco AJ, Gutierrez-Solana LG, Couce ML, Cancho-Candela R, Lázaro P, et al. Clinical practice guideline for the management of Hunter syndrome. Hunter España working group. Med Clin (Barc). 2013; 141(10):453.
How To Cite This Article : Dr A R Rajan, Dr Vikram Singh, Dr Anupama A Bhave, Dr Manish Saha, Dr Arindam Chatterjee Hunter Syndrome (MPS Type II) : A rare Clinical Entity Dr Vikram singh et al IJOMCR Volume 02 Issue 03 Jul-Sep p 05-09